Lipid-Extruded PEGylated Liposomes of Repurposed Sorafenib for Triple-Negative Breast Cancer: A Mechanistically Enhanced Nanoplatform with Improved In Vivo Pharmacokinetics and Targeted Biodistribution

Sorafenib Tosylate (SRT), a multikinase inhibitor originally approved for several solid tumors, has been repurposed for potential application in triple-negative breast cancer (TNBC) due to its multitargeted antitumor mechanisms. However, its clinical use is limited by poor aqueous solubility, low and variable oral bioavailability, rapid systemic clearance, and dose-limiting toxicities. To address these challenges, this study aims to develop SRT-loaded PEGylated liposomes prepared by solvent evaporation followed by a hydration method and optimized using a Box–Behnken design. A lipid extrusion process was employed to reduce vesicle size and enhance uniformity, yielding an average vesicle size of 104.5 ± 4.0 nm, a low PDI of 0.097 ± 0.004, and a high entrapment efficiency of 82.5 ± 2.2%. Comprehensive characterization confirmed successful encapsulation and crystalline-to-amorphous transition of SRT. In vitro evaluation demonstrated a controlled and sustained release profile, with PEGylated liposomes releasing 70.89 ± 4.9% over 48 h, compared to 96.8 ± 3.1% free SRT within 12 h. In vitro cytotoxicity assays on MDA-MB-231 cells showed enhanced anticancer activity (IC50 reduced from 35.63 ± 4.6 to 18.25 ± 1.8 μg/mL for 24 h), increased cellular uptake, ROS generation, and mitochondrial depolarization with PEGylated liposomes. Hemolysis assays confirmed excellent hemocompatibility, supporting the safety of intravenous administration. In vivo pharmacokinetic studies revealed a 5.6-fold increase in half-life and a 10.8-fold rise in AUC for PEGylated liposomes, alongside reduced hepatic and renal toxicity. Biodistribution studies demonstrated lower off-target organ accumulation, indicating improved circulation and stability. Overall, the lipid-extruded PEGylated liposome formulation overcomes key delivery limitations of SRT and offers a potent, safe, and effective platform for TNBC therapy.